Prediction of organophosphorus acetylcholinesterase inhibition using three-dimensional quantitative structure-activity relationship (3D-QSAR) methods. 2001

J El Yazal, and S N Rao, and A Mehl, and W Slikker
Division of Neurotoxicology, National Center for Toxicological Research/FDA, 3900 NCTR Road, Jefferson, Arkansas 72079, USA.

Neurotoxic organophosphorous compounds are known to modulate their biological effects through the inhibition of a number of esterases including acetylcholinesterase (AChE), the enzyme responsible for the degradation of the neurotransmitter acetylcholine. In this light, molecular modeling studies were performed on a collection of organophosphorous acetylcholinesterase inhibitors by the combined use of conformational analysis and 3D-QSAR methods to rationalize their inhibitory potencies against the enzyme. The Catalyst program was used to identify the structural features in the group of 8 inhibitors whose IC(50) values ranged from 0.34 nM to 1.2 microM. The 3-D pharmacophore models are characterized by at least one hydrogen bond acceptor site and 2-3 hydrophobic sites and demonstrate very good correlation between the predicted and experimental IC(50) values. Our models can be useful in screening databases of organophosphorous compounds for their neurotoxicity potential via the inhibition of acetylcholinesterase. Also, the pharmacophores offer an additional means of designing AChE inhibitors as potential therapeutic agents for central nervous system diseases.

UI MeSH Term Description Entries
D008958 Models, Molecular Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures. Molecular Models,Model, Molecular,Molecular Model
D008961 Models, Structural A representation, generally small in scale, to show the structure, construction, or appearance of something. (From Random House Unabridged Dictionary, 2d ed) Model, Structural,Structural Model,Structural Models
D008968 Molecular Conformation The characteristic three-dimensional shape of a molecule. Molecular Configuration,3D Molecular Structure,Configuration, Molecular,Molecular Structure, Three Dimensional,Three Dimensional Molecular Structure,3D Molecular Structures,Configurations, Molecular,Conformation, Molecular,Conformations, Molecular,Molecular Configurations,Molecular Conformations,Molecular Structure, 3D,Molecular Structures, 3D,Structure, 3D Molecular,Structures, 3D Molecular
D008970 Molecular Weight The sum of the weight of all the atoms in a molecule. Molecular Weights,Weight, Molecular,Weights, Molecular
D009447 Neuroblastoma A common neoplasm of early childhood arising from neural crest cells in the sympathetic nervous system, and characterized by diverse clinical behavior, ranging from spontaneous remission to rapid metastatic progression and death. This tumor is the most common intraabdominal malignancy of childhood, but it may also arise from thorax, neck, or rarely occur in the central nervous system. Histologic features include uniform round cells with hyperchromatic nuclei arranged in nests and separated by fibrovascular septa. Neuroblastomas may be associated with the opsoclonus-myoclonus syndrome. (From DeVita et al., Cancer: Principles and Practice of Oncology, 5th ed, pp2099-2101; Curr Opin Oncol 1998 Jan;10(1):43-51) Neuroblastomas
D009943 Organophosphorus Compounds Organic compounds that contain phosphorus as an integral part of the molecule. Included under this heading is broad array of synthetic compounds that are used as PESTICIDES and DRUGS. Organophosphorus Compound,Organopyrophosphorus Compound,Organopyrophosphorus Compounds,Compound, Organophosphorus,Compound, Organopyrophosphorus,Compounds, Organophosphorus,Compounds, Organopyrophosphorus
D011237 Predictive Value of Tests In screening and diagnostic tests, the probability that a person with a positive test is a true positive (i.e., has the disease), is referred to as the predictive value of a positive test; whereas, the predictive value of a negative test is the probability that the person with a negative test does not have the disease. Predictive value is related to the sensitivity and specificity of the test. Negative Predictive Value,Positive Predictive Value,Predictive Value Of Test,Predictive Values Of Tests,Negative Predictive Values,Positive Predictive Values,Predictive Value, Negative,Predictive Value, Positive
D002800 Cholinesterase Inhibitors Drugs that inhibit cholinesterases. The neurotransmitter ACETYLCHOLINE is rapidly hydrolyzed, and thereby inactivated, by cholinesterases. When cholinesterases are inhibited, the action of endogenously released acetylcholine at cholinergic synapses is potentiated. Cholinesterase inhibitors are widely used clinically for their potentiation of cholinergic inputs to the gastrointestinal tract and urinary bladder, the eye, and skeletal muscles; they are also used for their effects on the heart and the central nervous system. Acetylcholinesterase Inhibitor,Acetylcholinesterase Inhibitors,Anti-Cholinesterase,Anticholinesterase,Anticholinesterase Agent,Anticholinesterase Agents,Anticholinesterase Drug,Cholinesterase Inhibitor,Anti-Cholinesterases,Anticholinesterase Drugs,Anticholinesterases,Cholinesterase Inhibitors, Irreversible,Cholinesterase Inhibitors, Reversible,Agent, Anticholinesterase,Agents, Anticholinesterase,Anti Cholinesterase,Anti Cholinesterases,Drug, Anticholinesterase,Drugs, Anticholinesterase,Inhibitor, Acetylcholinesterase,Inhibitor, Cholinesterase,Inhibitors, Acetylcholinesterase,Inhibitors, Cholinesterase,Inhibitors, Irreversible Cholinesterase,Inhibitors, Reversible Cholinesterase,Irreversible Cholinesterase Inhibitors,Reversible Cholinesterase Inhibitors
D003198 Computer Simulation Computer-based representation of physical systems and phenomena such as chemical processes. Computational Modeling,Computational Modelling,Computer Models,In silico Modeling,In silico Models,In silico Simulation,Models, Computer,Computerized Models,Computer Model,Computer Simulations,Computerized Model,In silico Model,Model, Computer,Model, Computerized,Model, In silico,Modeling, Computational,Modeling, In silico,Modelling, Computational,Simulation, Computer,Simulation, In silico,Simulations, Computer
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man

Related Publications

J El Yazal, and S N Rao, and A Mehl, and W Slikker
January 2008, Journal of computational chemistry,
J El Yazal, and S N Rao, and A Mehl, and W Slikker
September 2004, Journal of molecular graphics & modelling,
J El Yazal, and S N Rao, and A Mehl, and W Slikker
January 2001, Journal of chemical information and computer sciences,
J El Yazal, and S N Rao, and A Mehl, and W Slikker
October 2007, Journal of medicinal chemistry,
J El Yazal, and S N Rao, and A Mehl, and W Slikker
December 2001, Bioorganic & medicinal chemistry,
J El Yazal, and S N Rao, and A Mehl, and W Slikker
August 1999, Drug design and discovery,
J El Yazal, and S N Rao, and A Mehl, and W Slikker
August 2000, Drug metabolism and disposition: the biological fate of chemicals,
J El Yazal, and S N Rao, and A Mehl, and W Slikker
August 1999, Pharmacogenetics,
J El Yazal, and S N Rao, and A Mehl, and W Slikker
June 2003, Bioorganic & medicinal chemistry,
J El Yazal, and S N Rao, and A Mehl, and W Slikker
December 2000, Nihon rinsho. Japanese journal of clinical medicine,
Copied contents to your clipboard!